US6700002B2 - Process for making vitamin E using hydrogen-tris(oxalato) phosphate - Google Patents

Process for making vitamin E using hydrogen-tris(oxalato) phosphate Download PDF

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US6700002B2
US6700002B2 US10/053,297 US5329702A US6700002B2 US 6700002 B2 US6700002 B2 US 6700002B2 US 5329702 A US5329702 A US 5329702A US 6700002 B2 US6700002 B2 US 6700002B2
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process according
reaction mixture
solvent
catalyst
isophytol
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US20020161247A1 (en
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Werner Bonrath
Thomas Netscher
Ulrich Wietelmann
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DSM Nutritional Products LLC
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Roche Vitamins Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols

Definitions

  • the present invention is concerned with a novel process for the manufacture of (all-rac)- ⁇ -tocopherol by the acid-catalyzed reaction of trimethylhydroquinone (TMHQ) with isophytol (IP) or phytol (PH) in a solvent.
  • TMHQ trimethylhydroquinone
  • IP isophytol
  • PH phytol
  • (all-rac)- ⁇ -tocopherol (or as it has mostly been denoted in the prior art, “d,l- ⁇ -tocopherol”) is a diastereoisomeric mixture of 2,5,7,8-tetramethyl-2-(4′,8′,12′-trimethyl-tridecyl)-6-chromanol ( ⁇ -tocopherol), which is the most active and industrially most important member of the vitamin E group.
  • a further interesting method for the manufacture of d,l- ⁇ -tocopherol from TMHQ and IP includes using an isolated TMHQ-BF 3 or —AlCl 3 complex and a solvent mixture featuring a nitro compound (DOS 1909164). This process avoids to a large extent the formation of undesired by-products because it involves mild reaction conditions.
  • the yield of d,l- ⁇ -tocopherol, based on IP and the use of the solvent mixture methylene chloride/nitromethane, is reported as 77%.
  • the use of such a solvent mixture is disadvantageous because nitro compounds tend to be unstable when excessively heated, so that difficulty is encountered in the product isolation, solvent separation and recycling procedures.
  • EP 603695 discloses the manufacture of d,l- ⁇ -tocopherol in liquid or supercritical carbon dioxide by the reaction of TMHQ with IP or PH in the presence of acidic catalysts, such as ZnCl 2 /HCl and ion exchangers. The reported yields are unsatisfactory.
  • An alternative for the reaction of TMHQ with IP to form d,l- ⁇ -tocopherol includes using trifluoroacetic acid or its anhydride as the catalyst (EP 12824). Although in this process the avoidance of HCl is achieved, the catalyst is also corrosive, and relatively expensive.
  • the reaction of TMHQ with IP to ⁇ -tocopherol can be achieved in high yields and with a high product purity when such solvents as carbonate esters, fatty acid esters and certain mixed solvent systems are employed, the exemplified catalysis being effected by ZnCl 2 /HCl. Disadvantages in this process are, in addition to the contamination of the waste water by zinc ions, the usual large “catalyst amount” of ZnCl 2 used.
  • the acid-catalyzed reaction of TMHQ with IP can be performed in a cyclic carbonate or ⁇ -lactone as the solvent.
  • the preferred catalyst is a mixture of orthoboric acid and oxalic, tartaric or citric acid, or boron trifluoride etherate.
  • EP 784042 there is disclosed the use of hydrogen bis(oxalato)borate as a protonic acid catalyst in various condensation reactions, e.g. Friedel-Crafts condensations, including the acid-catalyzed reaction of TMHQ with IP to produce d,l- ⁇ -tocopherol.
  • various condensation reactions e.g. Friedel-Crafts condensations, including the acid-catalyzed reaction of TMHQ with IP to produce d,l- ⁇ -tocopherol.
  • WO 98/21197 discloses the manufacture of d,l- ⁇ -tocopherol from TMHQ and IP using bis(trifluoromethylsulphonyl)imide or a metal salt thereof optionally together with a strong Bronsted acid, as catalyst in such types of aprotic solvents as aliphatic and cyclic ketones or esters, and aromatic hydrocarbons.
  • An object of the present invention is to provide a process for the manufacture of (all-rac)- ⁇ -tocopherol by the reaction of trimethylhydroquinone with isophytol or phytol in the presence of a catalyst and in a solvent which does not have the disadvantages of previously known procedures.
  • the catalyst used has no, or at least a much reduced, corrosive action, is non-toxic, does not contaminate the environment, e.g. with chlorinated by-products or heavy metal ions, and catalyzes the desired reaction as selectively as possible and in high yields.
  • the catalyst should display its activity in small, really catalytic, amounts and should be readily separable and re-usable several times.
  • One embodiment of the invention is a process for making (all-rac)- ⁇ -tocopherol comprising contacting a reaction mixture comprising trimethylhydroquinone and isophytol or phytol with a catalyst comprising hydrogen tris(oxalato)phosphate and an organic solvent or the reaction mixture.
  • the hydrogen tris(oxalato)phosphate used as the catalyst in the process in accordance with the present invention is a compound of the formula:
  • Said hydrogen tris(oxalato)phosphate may be produced by contacting phosphorus pentachloride with oxalic acid and an aprotic organic solvent.
  • the object of the present invention is achieved by carrying out the reaction of trimethylhydroquinone with isophytol or phytol in the presence of hydrogen tris-(oxalato)phosphate as the catalyst in an organic solvent.
  • reaction to form (all-rac)- ⁇ -tocopherol is represented in the following Reaction Scheme, showing the reaction with IP only:
  • the process in accordance with the present invention for the manufacture of (all-rac)- ⁇ -tocopherol by the catalyzed reaction of trimethylhydroquinone with isophytol or phytol is characterized by carrying out the reaction in the presence of hydrogen tris(oxalato)phosphate as the catalyst in an organic solvent.
  • the catalyst which has the following formula
  • This new catalyst may be produced very simply by reacting phosphorus pentachloride with oxalic acid in an aprotic organic solvent, whereby the hydrogen chloride gas generated in the reaction is removed from the reaction mixture. This reaction is represented by the equation:
  • the oxalic acid should be as anhydrous as possible, such as can be achieved by pre-drying treatment with a desiccating agent, e.g. according to well-known procedures.
  • the reaction for producing hydrogen tris(oxalato)phosphate can be effected in practice either by adding the phosphorus pentachloride to the oxalic acid in the solvent or by adding the oxalic acid to the phosphorus pentachloride in the solvent, the addition in each case being portionwise.
  • the aprotic organic solvent there is suitably used a lower aliphatic mono- or diether, e.g. diethyl ether or, respectively, dimethoxyethane; a cyclic ether, e.g.
  • tetrahydrofuran a lower dialkyl carbonate, e.g. dimethyl or diethyl carbonate; an alkylene carbonate, e.g. ethylene or propylene carbonate; a C 5-12 -alkane; an aromatic hydrocarbon, e.g. benzene or toluene; a partially or per-halogenated aliphatic or aromatic hydrocarbon; or a mixture of two or more of the aforementioned aprotic organic solvents.
  • both the reactants will be at least partially dissolved therein or present in suspension therein, e.g. in the latter case when a hydrocarbon is used as the solvent.
  • the reaction to produce the hydrogen tris(oxalato) phosphate is carried out in a temperature range from about ⁇ 20° C. to about +120° C., preferably at temperatures from about 0° C. to about 100° C.
  • the molar ratio of the oxalic acid to the phosphorus pentachloride is suitably 3.1 (equivalent proportions) or slightly higher, i.e. where the oxalic acid is in slight excess.
  • “slightly higher” or “in slight excess” means that no more than about 5% excess of oxalic acid is employed.
  • the generated hydrogen chloride can also be removed by liquid/liquid separation: in such a case the reaction mixture forms into two liquid phases, i.e. a lower, denser phase containing the desired hydrogen tris(oxalato)phosphate in the form of its ether complex with very little, i.e., less than 5 wt.
  • an inert gas e.g. nitrogen or argon
  • the upper phase can be removed from the lower phase, and the latter extracted one or more times with ether to remove any hydrogen chloride present.
  • the remaining oily phase consisting largely of the hydrogen tris(oxalato)phosphate diethyl etherate adduct (particularly of the formula [P ⁇ (C 2 O 4 ) 3 ]H + .4(C 2 H 5 ) 2 O), can then be subjected to reduced pressure drying at room temperature for several minutes to remove unbound ether solvent and at least some of the bound ether, if desired, whereby the oil transforms to a crystalline solid.
  • the exact composition of the adduct depends on the conditions of drying in each case.
  • a typical adduct with diethyl ether features on average about 2 molecules of diethyl ether per molecule of hydrogen tris(oxalato)phosphate.
  • the actual reaction to produce hydrogen tris(oxalato)phosphate is normally complete within several minutes to a few hours.
  • the catalyst can be used in the process for making (all-rac)- ⁇ -tocopherol without purification, and for example can be used despite containing some solvent remaining from its preparation, particularly because it may even be added in solution, for example in an aliphatic ether or a dialkyl or alkylene carbonate, for example the solvent in which the catalyst was prepared. Moreover, it may be used as its adduct with a solvent, particularly an aliphatic ether, such as diethyl ether, e.g.
  • Solvents which can be used with the present process include polar aprotic and non-polar organic solvents.
  • Suitable classes of polar aprotic organic solvents include aliphatic and cyclic ketones, e.g. diethyl ketone and isobutyl methyl ketone and, respectively, cyclopentanone and isophorone; cyclic esters, e.g. ⁇ -butyrolactone; and dialkyl and alkylene carbonates, e.g. dimethyl carbonate and diethyl carbonate, and respectively, ethylene carbonate and propylene carbonate.
  • Examples of classes of non-polar organic solvents that may be used in the process include aliphatic hydrocarbons, e.g.
  • reaction can be effected in a single solvent phase, especially in a polar aprotic organic solvent, e.g. in ⁇ -butyrolactone or propylene carbonate, alone as the solvent, or in a biphasic solvent system, especially one consisting of a polar aprotic organic solvent, e.g. ethylene and/or propylene carbonate, as the one phase and a non-polar organic solvent, e.g. heptane, as the other phase.
  • a polar aprotic organic solvent e.g. ethylene and/or propylene carbonate
  • non-polar organic solvent e.g. heptane
  • the process is conveniently carried out at temperatures from about 50° C. to about 150° C., preferably from about 90° C. to about 125° C., and most preferably from about 105° C. to about 120° C.
  • the molar ratio of trimethylhydroquinone to isophytol/phytol present in the reaction mixture conveniently extends from about 1:1 to about 2.5:1, preferably from about 1.5:1 to about 2.2:1, and is most preferably about 2:1.
  • the amount of catalyst used is such that the molar ratio of catalyst to the educt (trimethylhydroquinone or isophytol/phytol) which is in the lesser molar amount (usually the isophytol or phytol rather than the trimethylhydroquinone) is conveniently about 0.005:100 to about 4:100, i.e. the amount of catalyst is conveniently from about 0.005 mole % to about 4 mole % of the amount of educt present in the reaction mixture in the lesser molar amount.
  • the expression “amount of catalyst” means the weight of pure hydrogen tris(oxalato)phosphate, i.e. of the formula [P ⁇ (C 2 O 4 ) 3 ]H + , present, even though the catalyst may be impure and/or in the form of an adduct with a solvent, e.g. diethyl ether.
  • the process is carried out in a biphasic solvent system, especially one consisting of a polar aprotic organic solvent, e.g. an alkylene carbonate such as ethylene or propylene carbonate, and a non-polar organic solvent, e.g. an aliphatic hydrocarbon such as heptane, then the volume ratio of the non-polar solvent to the polar solvent is conveniently in the range from about 0.3:1 to about 5:1, preferably from about 1:1 to about 3:2.
  • a polar aprotic organic solvent e.g. an alkylene carbonate such as ethylene or propylene carbonate
  • non-polar organic solvent e.g. an aliphatic hydrocarbon such as heptane
  • the process is conveniently carried out under an inert gas atmosphere, preferably gaseous nitrogen or argon.
  • the actual reaction generally lasts for about 0.2 to about 20 hours, preferably about 0.5 to about 1 hour.
  • the process in accordance with the invention can be carried out batchwise or continuously, preferably continuously, and in general operationally in a very simple manner, for example by adding isophytol or phytol, as such, i.e. alone, in undiluted form, or in solution, portionwise to a suspension or solution of the trimethylhydroquinone and the catalyst.
  • the rate at which the isophytol or phytol is added is not critical.
  • isophytol/phytol is added continuously over a period of about 3 minutes to about 3 hours, preferably about 5 minutes to about 1.5 hours.
  • the working-up is effected by procedures conventionally used in organic chemistry.
  • the obtained (all-rac)- ⁇ -tocopherol can be converted into its acetate, succinate, poly(oxyethylene)succinate, nicotinate and further known application forms by standard procedures.
  • the process for forming (all-rac)- ⁇ -tocopherol in accordance with the invention enables the catalyst used to be separated readily and to be reused several times.
  • Advantages in the use of the catalyst in the process in accordance with the invention are, in addition to high yields of (all-rac)- ⁇ -tocopherol, the avoidance of corrosion, the avoidance of waste water contamination with heavy metal ions, the high selectivity as well as the enabled ready isolation of the produced (all-rac)- ⁇ -tocopherol from the mixture after reaction. Furthermore, the amount of dehydration products, so-called phytadienes, which tend to result from the action of acids on allylic alcohols such as isophytol and phytol, is kept to an acceptable minimum in the process of the present invention, as is also the amount of furan derivatives which tend to be produced as by-products in dl- ⁇ -tocopherol manufacture (see, for example, Bull. Chem. Soc. Japan 68, 3569-3571 (1995)).
  • the mixture was then allowed to cool to room temperature. From the resulting two-phase fluid the upper phase was separated off and the lower phase, containing the desired product, was washed five times with about 120 g of diethyl ether in each case. As in the previous procedure the analysis of the initially removed upper phase and the washings indicated that the acid content became rapidly less from the initially removed phase to the last washing phase.
  • the weight loss corresponded with the removal of one mole of diethyl ether per mole of hydrogen tris(oxalato)phosphate.
  • the product consisted of finely crystalline hydrogen tris(oxalato)phosphate in the form of its adduct with diethyl ether, of which the analysis indicated a phosphorus (P) content of 2.7 mmol per gram.
  • Jeffsol® is a 1:1 mixture of ethylene carbonate and propylene carbonate, commercially available from Huntsman Corp., P.O. Box 15730, Austin, Tex. 78761, USA/Antwerp 2030, Belgium.
  • Example 2 The procedure of Example 2 was repeated with the differences that various mole % amounts of catalyst were used (based on the amount of isophytol used), and the solvent was in all cases the biphasic solvent system 50 ml of Jeffsol® and 50 ml of heptane. The results are presented in the following Table 2.
  • Example 2 The procedure of Example 2 was repeated using various mole % amounts of catalyst, various biphasic solvent systems, and varying the time of addition of the isophytol (IP). The results are presented in the following Table 3.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrane Compounds (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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US10/053,297 2001-01-18 2002-01-17 Process for making vitamin E using hydrogen-tris(oxalato) phosphate Expired - Lifetime US6700002B2 (en)

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EP01101026 2001-01-18
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EP (1) EP1227089B1 (de)
JP (1) JP2002284776A (de)
KR (1) KR20020062203A (de)
CN (1) CN1190431C (de)
AT (1) ATE250596T1 (de)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070161823A1 (en) * 2004-02-04 2007-07-12 Fabrice Aquino Process for the preparation of methylheptenone

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19933898A1 (de) * 1999-07-22 2001-02-01 Chemetall Gmbh Tris(oxalato)phosphate, Verfahren zu deren Herstellung und deren Verwendung

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2230659A (en) 1938-09-28 1941-02-04 Merck & Co Inc Process of synthesizing alphatocopherol
GB811895A (en) * 1956-02-02 1959-04-15 Merck Ag E Improvements in or relating to esters of -a-tocopherol
US5886196A (en) 1996-01-12 1999-03-23 Roche Vitamins Inc. Method of catalyzing condensation reactions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2230659A (en) 1938-09-28 1941-02-04 Merck & Co Inc Process of synthesizing alphatocopherol
GB811895A (en) * 1956-02-02 1959-04-15 Merck Ag E Improvements in or relating to esters of -a-tocopherol
US5886196A (en) 1996-01-12 1999-03-23 Roche Vitamins Inc. Method of catalyzing condensation reactions

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CA 124:248655.* *
Lamande, et al., "Structure Et Acidite De Composes A Atome De Bore Et De Phosphore Hypercoordonnes," Journal of Organometallic Chemistry, vol. 329, pp. 1-29 (1987).

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070161823A1 (en) * 2004-02-04 2007-07-12 Fabrice Aquino Process for the preparation of methylheptenone
US7319172B2 (en) * 2004-02-04 2008-01-15 Dsm Ip Assets B.V. Process for the preparation of methylheptenone

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US20020161247A1 (en) 2002-10-31
DE60200037T2 (de) 2004-07-08
DK1227089T3 (da) 2004-02-02
DE60200037D1 (de) 2003-10-30
EP1227089A1 (de) 2002-07-31
JP2002284776A (ja) 2002-10-03
KR20020062203A (ko) 2002-07-25
EP1227089B1 (de) 2003-09-24
CN1365977A (zh) 2002-08-28
CN1190431C (zh) 2005-02-23
ATE250596T1 (de) 2003-10-15

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